Engineering an Anion-Binding Cavity in Antichymotrypsin Modulates the "Spring-Loaded" Serpin-Protease Interaction
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- 作者：Christine M. Lukacs ; Harvey Rubin ; and David W. Christianson
- 刊名：Biochemistry
- 出版年：1998
- 出版时间：March 10, 1998
- 年：1998
- 卷：37
- 期：10
- 页码：3297 - 3304
- 全文大小：145K
- 年卷期：v.37,no.10(March 10, 1998)
- ISSN：1520-4995
文摘
Expressed in a kinetically trapped folding state, aserpin couples the thermodynamic drivingforce of a massive 
-sheet rearrangement to the inhibition of atarget protease. Hence, the serpin-protease interaction is the premier example of a "spring-loaded"protein-protein interaction. Aminoacid substitutions in the hinge region of a serpin reactive loop canweaken the molecular spring, whichconverts the serpin from an inhibitor into a substrate. To probethe molecular basis of this conversion,we report the crystal structure of A349R antichymotrypsin in thereactive loop cleaved state at 2.1 Åresolution. This amino acid substitution does not block the-sheet rearrangement despite the burial ofR349 in the hydrophobic core of the cleaved serpin along with asalt-linked acetate ion. The inhibitoryactivity of this serpin variant is not obliterated; remarkably, itsinhibitory properties are anion-dependentdue to the creation of an anion-binding cavity in the cleavedserpin.
-sheet rearrangement to the inhibition of atarget protease. Hence, the serpin-protease interaction is the premier example of a "spring-loaded"protein-protein interaction. Aminoacid substitutions in the hinge region of a serpin reactive loop canweaken the molecular spring, whichconverts the serpin from an inhibitor into a substrate. To probethe molecular basis of this conversion,we report the crystal structure of A349R antichymotrypsin in thereactive loop cleaved state at 2.1 Åresolution. This amino acid substitution does not block the-sheet rearrangement despite the burial ofR349 in the hydrophobic core of the cleaved serpin along with asalt-linked acetate ion. The inhibitoryactivity of this serpin variant is not obliterated; remarkably, itsinhibitory properties are anion-dependentdue to the creation of an anion-binding cavity in the cleavedserpin.